Controllers are defined as individuals who control plasma HIV RNA levels to 2,000 copies or below for many years in the absence of highly active antiretroviral therapy (HAART). Our previous work revealed that many Controllers have unusually strong, polyfunctional HIV-specific CD8+ T-cell responses at tissue sites of viral replication, such as the gastrointestinal mucosa. Despite their ability to contain viral replication, these individuals form a heterogeneous group;at least some of whom ultimately progress to CD4 decline and AIDS-defining illnesses. In preliminary studies, HIV Controllers had significantly higher CSF viral loads than HIV+ patients on HAART with suppressed viremia (P<0.0001). Controllers also had elevated CSF neopterin and IP-10 relative to HIV negative individuals. Thus, some HIV Controllers have CSF viremia and elevated markers of CNS immune activation. These patients represent a unique opportunity to study the mechanisms contributing to immune control, and the balance between adaptive immunity and immune activation/inflammation in the CNS. This collaborative R21 proposal will draw on an unusually well characterized group of HIV Controllers and a group of clinical investigators in Immunology, Clinical Neurology, Imaging, and Neuropsychology to determine the extent of CNS inflammation and/or injury in HIV Controllers, and to identify correlates of controlled or active CNS infection in these individuals. We will focus on (a) HIV-specific immune responses;(b) markers of T-cell activation;(c) soluble CSF biomarkers of neuronal injury;(d) cerebral metabolite markers measured by 4 Tesla MRS;and (e) neuropsychological testing. In Specific Aim 1, we will examine the relationship between plasma and CSF viremia and HIV-specific T-cell responses in HIV Controllers and matched comparison groups (i.e., Non-Controllers with VL >10,000 vRNA copies/mL;HAART-suppressed individuals with VL <50 copies/mL;HIV negative controls). In Specific Aim 2, we will examine the relationship between the parameters assessed in Aim 1 and biomarkers of inflammation/immune activation, neurological damage, and clinical status in the same subject groups. The studies in this proposal will determine the extent of CNS involvement in HIV Controllers, and investigate the immunological mechanisms underlying control of local CNS infection in the absence of HAART. Identification of correlates of immune control in the CNS in this unique group of subjects may facilitate the development of therapies that can mitigate or arrest the injurious effects of HIV in the CNS in all HIV-infected subjects. PUBLIC HEALTH RELEVANCE: HIV Controllers represent a unique group of individuals who control plasma HIV RNA levels in the absence of highly active antiretroviral therapy (HAART). Nevertheless, some HIV Controllers experience CD4 T-cell decline and disease progression. The goal of this project is to determine the extent of central nervous system (CNS) involvement in HIV controllers, and investigate the immunological mechanisms underlying control of local CNS infection in the absence of HAART.